Infants born to mothers who used cocaine during pregnancy have not only an increased incidence of mortality and morbidity, but also functional neurological and behavioral abnormalities. Cocaine potentiates the actions of the catecholamines, which serve special roles in the perinatal period as trophic factors regulating cellular development of central and peripheral adrenergic target tissues, as well as mediating physiological adaptations through specialized, neonatal mechanisms. Thus, prenatal cocaine exposure could not only disrupt the development and function of the nervous system and adrenergic target tissues but also compromise neonatal viability. This proposal will address two key questions: 1. How are cellular replication and differentiation in the central nervous system and its targets affected by fetal cocaine exposure and do these effects result in temporary and/or long-term dysfunction? 2. Does fetal cocaine exposure increases infant mortality by impairing unique neonatal mechanisms necessary to survival? The effects of continuous (throughout gestation) maternal cocaine administration will be examined, followed by studies to identify critical periods for fetal exposure and to establish threshold exposure levels. For each case, profiles for replication and differentiation of the central nervous system and of a peripheral sympathetic pathway (cardiac - sympathetic axis) will be assessed using biochemical indices of cellular maturation (ornithine decarboxylase, polyamine, nucleic acid and protein levels and synthesis rates). This will be followed by examining the ontogeny of pre- and postsynaptic elements (catecholamine levels, amine uptake systems, biosynthetic enzymes, receptor binding sites), of target tissue responsiveness (adrenergic receptor mediated responses to selective agonists) and of presynaptic function (development of transmitter turnover and release). Finally, the ability of 1 day old rat to tolerate hypoxia will be examined, together with the development of the adrenal medulla (catecholamine levels, non-neurogenic catecholamine release capability, onset of functional innervation to the adrenal). This is likely to be compromised by prenatal cocaine exposure, and is particularly important because the organism's ability to withstand the extended periods of hypoxia associated with birth is dependent largely upon circulating catecholamines released from the adrenal medulla. The amines act at adrenergic receptors present in neonatal end-organs to preserve vital functions such as maintenance of cardiac conduction (assessed by heart rate and EKG).
